Abstract

In this study naltrindole (NTI) and its benzofuran derivative (NTB) were studied for their antagonist activity against various delta opioid receptor agonists in the tail-flick antinociceptive assay in mice. The antinociceptive ED50 of i.c.v. administered DSLET [(D-Ser2, Leu5, Thr6)enkephalin] was shifted about 4-fold by either s.c. NTB or i.c.v. NTI injection. On the other hand, the antinociceptive ED50 of i.c.v. administered DPDPE [(D-Pen2,D-Pen5)enkephalin] was shifted 1.4- and 1.8-fold with s.c. NTB and i.c.v. NTI administration, respectively, which were significantly lower than the shifts observed with DSLET. NTB did not alter the antinociceptive action of i.c.v. administered [(D-Ala2,D-Leu5)enkephalin], morphine sulfate, [(D-Ala2,MePhe4,Gly-ol5)enkephalin] or U-50,488H (trans(+/-)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl) cyclohexyl]benzeneacetamide). At spinal sites, the antinociceptive ED50 of intrathecal (i.t.) administered DSLET was increased by 12.5-fold by s.c. NTB injection, whereas that of DPDPE was unaffected. NTB injection at this site also did not alter the antinociceptive action of i.t. administered [D-Ala2, D-Leu5]enkephalin, [(D-Ala2,MePhe4,Gly-ol5)enkephalin] or morphine sulfate. Pretreatment of animals with beta-funaltrexamine caused a large increase in the capacity of NTB to antagonize the antinociceptive activity of i.t. administered DSLET with little change in that of i.t. administered DPDPE. When cross-tolerance between DSLET and DPDPE was studied by i.c.v. injection of a single large dose of either DSLET or DPDPE 24 hr before the antinociceptive assay, there was no development of cross-tolerance between the two peptides. Based on these results, it was concluded that the antinociceptive action of DSLET and DPDPE may be mediated by different receptors, possibly delta opioid subtypes.